What is Alzheimer’s?
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a decline in cognitive function and a progressive loss of memory sufficient to interfere with daily function. It was first introduced at a conference in which Alois Alzheimer gave a report of one of his female patients who in middle age experienced a change in personality, followed by memory loss, confusion, and disorientation to the extent that she could no longer find her way around the house. This was in 1906. And now, almost a century later, the illness, in many ways, remains a mystery.
There is, however, a fair amount that is known. It is primarily a disease of the elderly, its prevalence doubling every five years to a level of 30% to 50% by the age of 85. It is an illness that progresses gradually. Patients often misplace various items repeatedly, show a decline in job performance, forget directions to previously familiar locations, struggle to come up with appropriate words while speaking, and become increasingly passive and aloof. Ultimately, these patients lose the capacity for functioning autonomously and, therefore, they are forced into complete dependency. They deteriorate into a vegetative state, become bedridden, and die often from infections or pulmonary embolus.
While the complete pathogenesis of the illness remains unknown, however, some elements of its pathology are clear. The etiological search for any illness begins with its cellular pathology, and what is found on examination of Alzheimer’s brains is a loss of neurons in regions of the cerebral cortex and the hippocampus, ultimately leading to diffuse atrophy in those areas.
There are two defining characteristics of AD neuropathology that are believed to play a causative role in the disease: neurofibrillary tangles and neuritic plaques. Neurofibrillary tangles are bundles of filaments that collect inside the neurons. These are paired helical filaments composed of a hyperphosphorylated form of a protein called tau. These tau proteins begin to accumulate within the neurons prior to the development of the plaques and they are believed to somehow cause the death of these neurons. Neuritic plaques (also referred to as senile plaques) are aggregates of axons and dendrites (collectively referred to as neurites), microglia, and astrocytes surrounding a core of amyloid, a fibrillary protein that is deposited in tissues during certain pathological conditions. The presence of both is required for a definitive pathologic diagnosis of AD.
It is, however, important to note that while neurofibrillary tangles are found in illnesses other than AD (i.e., progressive supranuclear palsy and Parkinson’s disease), neuritic plaques are almost unique to AD and to normal aging. These neuritic plaques have, therefore, been the primary target of therapeutics, and so a further word on their nature is warranted.
As stated earlier, microglia and astrocytes form a part of the neuritic plaques. These are cells that travel to sites of brain injury for purposes of restoration and repair. They, along with the neurites, aggregate around a core of amyloid of the beta-type (commonly denoted as AB). The most predominant form of beta amyloid found in these plaque cores is the 42-amino-acid form (beta amyloid-42).
What is beta amyloid?
Beta amyloid is a protein produced by all cell types and it is derived from a cleavage of its metabolic precursor, amyloid precursor protein (APP). Its aggregation in the brain, whether diffusely or within amyloid cores of neuritic plaques, is a cardinal feature of AD, and its amount in the brain correlates with the patient’s cognitive impairment. The evidence suggests that beta amyloid is toxic to neurons. It is, therefore, possible that the toxic reactions during which the protein begins to affect neurons incite a potent immune response within the brain. This process seems to continue for years while the brain tissue suffers from chronic toxicity and inflammation leading to neuronal death and, therefore, functional decline.
Regardless of the pathophysiologic details, one point seems to be clear: beta amyloid plays a role in the development of AD. Genetic mutations associated with the development of AD have been elucidated: APP gene on chromosome 21, presenilin-1 gene on chromosome 14, and the presenilin-2 gene on chromosome 1. These mutations cause AD, and it is interesting to note that every one of them has the effect of beta amyloid overproduction. It should, therefore, come as no surprise that much of the therapeutic attention is focused on this important protein-the vaccine being a case in point.
So do we really have a vaccine?
Don’t know. PDAPP transgenic mice were used for the study. In other words, these were mice that were engineered to overexpress the human form of mutant APP which, as it does in humans, contributes to the production of the neuropathologic changes characteristic of AD. When the mice were six weeks of age, and prior to the formation of any brain plaques, they were given one of two solutions: a buffer containing beta amyloid-42 or a buffer containing another plaque-associated protein called serum amyloid-P component (SAP). Two additional groups were given either buffer alone or nothing at all and they served as the experiment’s controls. The solutions were administered as 11 immunizations over 11 months. Beta amyloid and SAP were, therefore, the two immunogens in the study (in that they were the substances capable of inciting an immune response).
Upon examination of the mouse brains at 13 months, seven of the nine mice immunized with beta amyloid were free of beta amyloid deposits and of dystrophic neurites. The brains of the control and SAP-treated mice harbored numerous beta amyloid deposits and neuritic plaques. In addition, the brains of the beta amyloid-treated mice displayed a dramatic reduction in the level of astrocytosis, while those of the other groups of mice exhibited a pattern of astrocytosis typical of AD. Further evidence in favor of beta amyloid involves a study of MAC-1, a cell-surface receptor that is upregulated on activated, plaque-associated microglial cells. Using a MAC-1-specific antibody, the researchers found a paucity of receptor labeling in the beta amyloid-treated mouse brains as compared to those of the other mice. Since inflammation plays a role in the development of AD neuropathology, and since microglia are at the very center of this inflammatory process, this finding seems to be of some importance.
Following this phase of the study there still loomed a larger question: What about the possibility of reversing any preexisting neuropathology?
PDAPP mice were immunized on an ongoing basis with beta amyloid-42 and adjuvant (a substance used to boost the immune response) at 11 months of age, an age by which their brains usually already harbor beta amyloid plaques. Another group of PDAPP mice was given buffer plus adjuvant and it served as the control.
Mouse brains from both groups were examined after four and seven months of treatment. The amount of beta amyloid (termed the beta amyloid burden) was significantly lower in the brains of beta amyloid-treated mice as compared to those of the controls. The number of plaques was also considerably reduced in the beta-amyloid-treated mice as compared to the controls. Neuritic plaque burden was reduced by 84% in the brains of the beta amyloid-treated mice as compared with controls. Astrocytosis was also considerably reduced in the brains of the beta amyloid-treated mice. Following three months of treatment, amyloid-plaque pathology varied from a great reduction to a virtual absence in those structures of the brain that are progressively affected in AD brain. These results, therefore, suggest that the beta amyloid-42 immunization proved effective in somehow halting the progress of the beta amyloidosis so typical of AD brain.
The researchers have established that immunization with beta amyloid-42 triggers the production of antibodies against the beta amyloid-42. They have also found that this immunization has no effect on beta amyloid production. They, therefore, speculate that the anti-beta amyloid antibodies produced in response to the immunization facilitate the clearance of beta amyloid via the assistance of microglial cells either prior to beta amyloid deposition or following plaque formation. Therefore, the researchers assess that immunization with beta amyloid-42 may prove effective in not only the prevention but also the treatment of AD.
Although several questions remain unanswered, the study may prove useful in conjunction with future experiments in humans.
Thus far, the beta amyloid discussion has focused on its potential immunogenic role in contributing to the pathophysiology of AD. Of the several possible roles the protein may play in the development of AD, there is another that has been given a considerable amount of attention: the generation of free radicals.
What is a free radical?
A free radical is a molecule with an uneven number of electrons. This feature renders the molecule highly reactive, and in many cases, dangerous to various tissue environments.
One such creature is superoxide, a highly reactive form of oxygen that is formed when oxygen is reduced by a single electron. This superoxide radical can cause injury to neurons and other cells producing various degenerative changes in the tissue.
Much attention has been given to free radical generation and the aging phenomenon (a hypothesis known as the free-radical theory of aging), and since AD is a disease associated with aging, the relation between free radicals and the hallmark protein of AD, beta amyloid, has been the focus of recent study.
It has been found that beta amyloid has a constrictive effect on blood vessels. In order to elucidate the role, if any, of free radicals in the development of such an effect, researchers studied the effect of adding an enzyme that scavenges superoxide, known as superoxide dismutase (SOD), to the experiment. They found that pretreatment with SOD was effective in eliminating the vasoconstriction seen with beta amyloid, a finding that suggests that beta amyloid’s constrictive effect is mediated through the superoxide free radical. In another experiment the same scientists pretreated the tissue with beta amyloid and then added acetylcholine, a vasodilator. They found that the beta amyloid reduced the vasodilation induced by the acetylcholine. As a follow up they washed beta amyloid off of the tissue and found that this did not restore blood vessel relaxation to the same level as controls that received acetylcholine alone. This finding, then, suggests that beta amyloid has the effect of altering the endothelium, the cells that line the blood vessels.
The scientists studied the vessels ultrastructurally and found them damaged as a result of their exposure to beta amyloid. However, pretreatment with SOD prevented such damage as well as the vasoconstriction seen in the absence of SOD.
In addition to these findings, the report highlights the possibility that beta amyloid contact with endothelium could result in free radical-mediated endothelial damage, resulting in a reduction in local blood flow and heightened oxidative stress leading to potential tissue damage.
So how do we eliminate free radicals?
In a word, antioxidants. There are endogenous and exogenous antioxidants that either block free radical formation or scavenge free radicals after they have formed. Alpha tocopherol (vitamin E) works via the latter mechanism.
There have been several studies addressing the efficacy of vitamin E on the improvement of AD symptamotology. The purpose of one such study was to test the ability of the vitamin and that of a monoamine oxidase inhibitor, selegiline, to delay the occurrence of the primary outcome of disease progression: death, institutionalization, loss in the ability to perform activities of daily living, or severe dementia. It was a double-blind, placebo-controlled, randomized study involving 341 patients with probable AD of moderate severity. They were divided into four groups and given one of four medications: selegiline, vitamin E, selegiline and vitamin E, or placebo.
Researchers found that treatment with vitamin E, selegiline, or a combination of both was effective in delaying the primary outcome of disease progression as compared to placebo, particularly with respect to institutionalization, performance of activities of daily living, and the need for care. The delay in the need for institutionalization was seen primarily in the vitamin E group. They also found no significant therapeutic differences between the groups that received combination treatment and those that received one or the other alone.
Therefore, antioxidation may serve as a useful therapeutic approach in Alzheimer’s patients.
Bacteria and Alzheimer’s
A recent report has added an interesting twist to the Alzheimer’s debate. A bacterium has been found in the postmortem brain tissue of Alzheimer’s patients. Chlamydia pneumoniae, a bacterium that causes respiratory infections such as pneumonia, was isolated from those regions of the brain that showed AD-related neuropathology.
Brain tissue of 19 AD patients and those of 19 controls (non-AD patients) were used in the study. Assays specific for Chlamydia pneumoniae DNA were used to test for the presence of the bacterium. The researchers found that of 19 AD patients, 17 of them harbored brain regions that were positive for the bacterium, while only 1 of the 18 non-AD patients demonstrated this. More importantly, the researchers found that within the majority of AD brains the bacterial DNA was far more common in the regions of neuropathology than in the unaffected regions of the same brain. However, conclusive evidence of bacterial presence is best demonstrated by culturing the organism. Using specific cell lines that have been shown to be effective hosts for C. pneumoniae infection the researchers were successful in culturing the bacterium. They also demonstrated by electron microscopy the presence of the organisms within these host cells. Once again, they found the bacteria absent in similar tissues from non-AD patients.
So what does this mean?
Well, on the face of it one might assume that C. pneumoniae plays some etiologic role in the development of AD. They may be right. Or they may not be.
The fact is this observation, for the time being, remains an observation, as no causal role has been established between AD and this organism. However, it does raise some possibilities. For instance, if in these patients infection by C. pneumoniae is a chronic one, it could elicit a chronic inflammatory response that over time might contribute significantly to the neuropathology of AD as we know it.
The researchers, therefore, contend that infection of the central nervous system by C. pneumoniae may represent an important risk factor for the development of sporadic, late-onset AD.
As should now be clear, AD is a multifaceted illness with numerous pathologic manifestations and a defined clinical symptamotology. However, which of these pathologies lead to the different types of cognitive decline? By what mechanisms do these pathologies result? What is the inciting factor that triggers the initiation of the pathophysiology?
Although there has been a great deal of scientific progress in the area of AD, such fundamental questions, in some sense, remain as prominent today as they were in 1906. As these studies show, however, medicine is on the very cusp of discovery and the future for AD patients is well served by the plethora of research that is currently in progress.
As for the beta amyloid vaccine, it must be said that mice are mice and, therefore, more questions need to be answered. The study, however, is an interesting one. If scientists prove the research to work in humans, it would represent an enormous breakthrough for medical science and for the scientists who would, no doubt, find their names in bold text next to those of Pasteur, Salk, and of course, Alzheimer.
Source: LE Magazine December 1999
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